Metabolic diseases or disorders are caused by an abnormal metabolic process and can either be congenital due to an inherited enzyme abnormality or acquired due to a disease of an endocrine organ or failure of a metabolically important organ such as the liver or the pancreas.
Among the metabolic disorders, diabetes mellitus is the most prevalent and is considered to be one of the five leading causes of death in the world (Diabetes Care, 2004, vol. 27, 1047-1053). According to the National Diabetes Statistics Report (2014), around 29.1 million people or 9.3% of the population in the United States have diabetes. Diabetes mellitus is typically classified into two main subtypes: Type 1 and Type 2 diabetes mellitus. Type 1 diabetes mellitus (also known as Insulin Dependent Diabetes Mellitus or IDDM), which generally occurs in adolescents under 20 years of age, is an auto-immune disease causing an insulitis with the subsequent destruction of insulin-producing β-cells of the pancreas. Further, in latent autoimmune diabetes in adults (LADA), β-cells are destroyed due to autoimmune attack. The subsequent lack of insulin leads to elevated levels of blood and urine glucose (hyperglycemia). Although the exact trigger for this autoimmune response is not known, patients with Type 1 diabetes have high levels of antibodies against pancreatic beta cells (hereinafter “beta cells”). However, it cannot be ascertained that all patients with high levels of these antibodies develop Type 1 diabetes. Type 2 diabetes mellitus or non-insulin-dependent diabetes mellitus (NIDDM) is developed when human muscle, fat and liver cells are not able to respond normally to insulin that the body secretes. This inability to respond, otherwise known as insulin resistance, can be due to restriction on the numbers of insulin receptors on these cells, or a dysfunctional behaviour of signalling pathways within the cells, or both. Initially, the β-cells which are responsible for the production of insulin, compensate for this insulin resistance by increasing their insulin secretion. However, these cells gradually become unable to produce enough insulin to facilitate the normal glucose homeostasis, causing the progression to Type 2 diabetes (Am. J. Med. 2000, 108(6), Supplement 1, 2S-8S). Type 2 diabetes (T2D) is characterised by fasting hyperglycemia which occurs as an effect of the combined lesions of insulin resistance and β-cell dysfunction. There are two types of defects associated with the β-cells: the first component, an increase in the basal insulin release which usually occurs in the presence of low, non-stimulatory glucose concentrations. The second component is a failure to enhance the insulin release in response to a hyperglycaemic challenge.
Obesity is another risk factor for developing metabolic diseases or disorders such as diabetes, cardiovascular disorders, hypertension, hyperlipidemia and an increased mortality. Diabetes caused by insulin resistance and obesity are part of the “metabolic syndrome” which is defined as the linkage between several diseases (also referred to as syndrome X, insulin-resistance syndrome, or deadly quartet). These often occur in the same patients and are major risk factors for the development of Type 2 diabetes and cardiovascular diseases (Frontiers in Endocrinology, 2013, vol. 4, 1-11). It has been suggested that the control of lipid levels and/or glucose levels is required to treat type 2 diabetes and cardiovascular diseases. Even though lifestyle changes like exercise and healthy diet are regarded as the most efficient ways to prevent and manage the diseases, pharmaceutical intervention is frequently necessary.
Current treatment options for diabetes, particularly T2D, include use of hypoglycaemic agents and insulin. Metformin is one such hypoglycemic agent which is used in the treatment of Type 2 diabetes. It is, in fact, one of the oldest drugs used for the treatment of T2D and it still remains the drug of choice despite associated gastrointestinal (GI) side effects including anorexia, nausea, diarrhea and vomiting commonly associated with it. Sulfonylureas (SUs) e.g. glimepiride, glipizide, are insulin secretagogues, which act on β-cells to increase insulin release, are commonly used in the treatment of Type 2 diabetes. However, use of sulfonylureas is also associated with adverse effects in that they increase the risk of hypoglycaemia and lead to weight gain. Insulin treatment also carries the same side-effects. Thiazolidinedione compounds e.g. rosiglitazone, pioglitazone, are insulin sensitizers which bind to peroxisome proliferator-activated receptors (PPARs) in cells and thereby increase the insulin sensitivity. Though, thiazolidinedione compounds have also been widely used, the enhanced risks of cardiovascular disease and hepatotoxicity have resulted in stringent limitations on their use. Relatively recently, regulatory authorities approved new classes of anti-diabetic agents such as glucagon-like peptide-1 (GLP-1) agonists (exenatide and liraglutide) and dipeptidyl peptidase-4 (DPP-4) inhibitors (linagliptin and alogliptin).
It is a known fact that metabolic processes are regulated by fatty acids which are important biological molecules that serve both as a source of energy and as signalling molecules. Generally, it is believed that fatty acids produce their biological effects through interacting with intracellular targets including, for example, the family of peroxisome proliferator-activated receptors (PPARs). However, in the recent years it has become clear that fatty acids also serve as agonists for a group of cell surface G protein-coupled receptors (GPCRs). Free fatty acids (FFAs) have been demonstrated to act as ligands of several GPCRs including GPR40 (FFAR1), GPR43, GPR84, GPR119 and GPR120. One of the GPCR namely GPR40 facilitates glucose-stimulated insulin secretion from pancreatic β-cells, whereas the other GPCR namely GPR120 regulates the secretion of GLP-1 in the intestine, as well as insulin sensitivity in macrophages.
Among GPCRs, GPR120 is localized to intestinal enteroendocrine cells, such as colonic L cells. It is reported that GPR120 is a nutrient sensor that is activated endogenously by both saturated and unsaturated long chain fatty acids and that an altered glucagon axis contributes to the impaired glucose homeostasis. Thus, targeting GPR120 for diabetes can impact glucose homeostasis in part through altering glucagon secretion and islet function (J. Biol Chem., 2014, 289 (22):15751-15763).
GPR120 is reported as a target for the treatment of type 2 diabetes, obesity, and other metabolic diseases and also, for inflammatory disorders (J. Med. Chem. 2012, 55, 4511-4515; Trends Pharmacol Sci. 2011, vol. 32(9), 543-550). An expression of GPR120 in the gut epithelium reports indicating a putative role of GPR120 as a sensor of dietary fat (PLOS one, 2014, 9(2), e88227). Certain research studies conducted relatively recently identified that loss-of-function of GPR120 human variant is associated with obesity, diabetes and other insulin resistance, and related metabolic disorders and also with inflammatory disorders.
Various patent documents describe compounds which are reported to be GPR120 modulators. Examples of patent documents describing GPR120 modulators include PCT application publications WO2014059232, WO2013185766, WO2013139341, WO2011159297, WO2010080537, WO2009054479 and WO2005086661 and US application publications US2014069963, US2013217781 and US20110313003.
Thus, in view of the role of GPR120 receptor in potentiating or causing metabolic disorders such as diabetes and related disorders and also, inflammatory disorders, there is need in the art to develop compounds that act by modulating the GPR120 receptor pathways.